The purpose of this project is to identify the determinants of non- insulin-dependent diabetes (NIDDK), various types of arthritis, and gallbladder disease, and elucidate the natural history of the diseases. Genetic and environmental risk factors for NIDDM have been studied in the Pima Indians. The residents of the study area, approximately 5000 people, have participated in a longitudinal population study since 1965, allowing observations of the natural history of diabetes mellitus. Risk factors for obesity, hypertension, and cholelithiasis are also studied, along with the relationships of these diseases to diabetes and their effects on mortality rates. The genetics of diabetes is studied by means of family studies and relationships of genetic markers to disease. The roles of obesity, serum insulin concentrations, impaired glucose tolerance, occupational and leisure-time physical activity and diabetes in relatives are assessed. Birth weight was found to be related to subsequent risk of diabetes in adulthood, with those of low (less than 2.5 kg) and high (at least 4.5 kg) birth weights having a higher risk than those of intermediate birth weights. A proposed explanation is selective survival in infancy of those genetically predisposed to insulin resistance and diabetes. The risk of diabetes in adolescence and young adulthood is greater in persons with a parent with diabetes and diabetic renal disease than in those whose parents have diabetes without renal disease. The results are compatible with the hypothesis that multiple loci (or homozygosity at a single locus) determine the severity of diabetes and the likelihood of developing renal disease. Although the degree of overweight (or body weight relative to height) is a strong predictor of diabetes in the Pimas, a study of weight fluctuation (or departure from a linear change in weight over time) was not associated with risk of diabetes. Thus, concern about weight fluctuation should not deter clinicians from advising weight loss for diabetes prevention. Studies of the familial pattern of obesity suggest the influence of a major gene, but with additional influences or recent changes in environmental or behavioral factors.